Novel imidazoazines and imidazodiazines

ABSTRACT

Novel imidazopyridines, -pyrazines, -pyrimidines and -pyridazines having a 3-amino-2-OR-propoxy substituent, are disclosed. The compounds have β-adrenergic blocking activity.

BACKGROUND OF THE INVENTION

This is a division of application Ser. No. 796,958, filed May 16, 1977,now U.S. Pat. No. 4,166,851 granted Sept. 4, 1979.

The present invention involves imidazoazine and diazine compounds havingan 3-amino-2-OR-propoxy substituent. The compounds have pharmacologicalactivity exemplified by β-adrenergic blockade.

Condensed ring hetero cyclic compounds having an aminohydroxypropoxysubstituent are known as β-adrenergic blocking agents [Crowther et al.,J. Med. Chem., 260-266 (1972)].

It has now been discovered that certain novel 3-amino-2-OR-propoxysubstituted imidazoazines and imidazodiazines have pharmaceuticalactivity including β-adrenergic blockade.

SUMMARY OF THE INVENTION

Imidazopyridines, imidazopyrimidines, imidazopyrazines andimidazopyridazines having a 3-amino-2-OR-propoxy substituent and theirpharmaceutical use.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

An embodiment of this invention is compounds having the formula ##STR1##and pharmaceutically acceptable salts thereof wherein Z is --CH₂ --CHOR₃ --CH₂ --NHR₄ wherein R₃ is H or C₂ -C₁₂ acyl and R₄ is C₁ -C₁₂alkyl,

R is H, --SCF₃, --CN, halogen, C₁₋₆ alkyl, NH₂, C₁ -C₆ haloalkyl, C₁-C₁₂ acyl, phenyl, --COOR₅ wherein R₅ is H, C₁ -C₆ alkyl or C₆ -C₁₂carbocyclic aryl, --CONR₆ R₇ wherein R₆ and R₇ when separate, are H orC₁ -C₆ alkyl and when joined, are --CH₂ --(CH₂)₃ --CH₂, --CH₂ --CH₂--O--CH₂ --CH₂ --, --CH₂ --CH₂ --NH--CH₂ --CH₂ --, or --CH₂ --CH₂--N(CH₃)--CH₂ --CH₂ --, C₁ -C₆ alkylthio, C₁ -C₆ alkylsulfinyl or C₁ -C₆alkylsulfonyl, and

R₁ and R₂ when separate are R and when joined are --(CH₂)_(n) -- whereinn is 3,4 or 5.

The ring positions are numbered as shown within Formula I.

The pharmaceutically acceptable salts are the acid addition salts of theformula I-V free bases. Suitable acids include organic as well asinorganic acids. Examples of useful organic acids are carboxylic acidssuch as acetic acid, pamoic acid, maleic acid, succinic acid, citricacid, tartaric acid, oxalic acid, malic acid, pivalic acid, heptanoicacid, lauric acid, propanoic acid, pelargonic acid, oleic acid and thelike, and non-carboxylic acids such as isethionic acid. Examples ofuseful inorganic acids are the hydrogen halides i.e. HCl, HBr, HI,phosphoric acid, sulfuric acid, and the like. The hydrohalide salts,especially the hydrochlorides and maleic acid salts, especially thehydrogen maleate, are preferred.

Suitable R, R₁ and R₂ (when separate) substituents include H, NH₂, SCF₃,phenyl, cyano, halogen e.g., Cl, Br, I or F, C₁ -C₆ alkyl e.g., methyl,t-butyl, isoamyl, n-hexyl and the like; halo- C₁₋₆ alkyl such asω-chlorohexyl, bromopropyl; 1,2-dibromoethyl, 2,3-dichlorobutyl, --CF₃,--CBr₃, --CH₂ F, --CHCl₂ and the like; C₁₋₁₂ acyl of the formula##STR2## wherein L is H, alkyl e.g., CH₃, undecyl, isobutyl,5-ethyl-n-pentyl, ethyl or aryl e.g., phenyl, ##STR3## naphthyl,indanyl, p-tolyl and the like; the carboxy group and ester and amidederivatives thereof, the C₁ -C₆ alkylthio, sulfinyl and sulfonylderivatives thereof. The ester groups are C₁ -C₆ -alkylester exemplifiedby --COOCH₃, --COOC₆ H₁₃, --COOCH(CH₃)₂, --COOC₂ H₅ and the like and C₆-C₁₂ arylester, preferably carbocyclic aryl, exemplified by C₆ H₅ --OOC,p--CH₃ --C₆ H₄ --OOC--, C₆ H₅ --C₆ H₄ --OOC--, C₁₀ H₇ --OOC-- and thelike. The amide groups include --CONH₂, C₁ -C₆ substituted amide groupssuch as --CON(CH₃)₂, --CON(C₆ H₁₃)₂, --CONHC₂ H₅, --CON (sec. butyl)₂and the like and carbonyl heterocyclic groups such as ##STR4## The C₁-C₆ alkyl-thio, -sulfinyl and -sulfonyl groups are exemplified by CH₃--S--, C₆ H₁₃ --S, (CH₃)₃ C--S--, (CH₃)₂ CH--SO--, CH₃ --SO₂ --, C₂ H₅--SO₂ --, C₆ H₁₃ --SO; C₅ H₁₁ --SO--, sec.-butyl-SO₂ and the like. Thepreferred R, R₁ and R₂ (when separate) groups are hydrogen, haloalkyl,especially CF₃, cyano, alkyl especially methyl, halogen especially Cland Br, alkylthio especially --SCH₃ and phenyl.

R₁ and R₂ may also be joined forming the alkylene group --(CH₂)_(n) --where n is 3, 4 or 5 preferably 3 or 4 and more preferably 4.

R₃ may be hydrogen or C₂₋₁₂ acyl, The C₂₋₁₂ acyl groups include alkanoylgroups such as acetyl, pivaloyl, dodecanoyl, hexanoyl, succinoyl and thelike-- and carbocyclic aroyl groups such as benzoyl, 1- or 2-naphthoyl,p-methylbenzoyl, p-phenylbenzoyl and the like. The C₂ -C₆ alkanoyl andbenzoyl groups are preferred acyl groups. Compounds where R₃ is hydrogenare preferred.

The R₄ substituent includes C₁ -C₁₂ alkyl groups and preferably the C₁-C₆ alkyl groups. The alkyl groups are exemplified by methyl, C₁₂ H₂₅--, hexyl, 2-ethylhexyl, isopropyl, sec-butyl, heptyl and the like. TheC₃₋₄ branched chain alkyl R₄ groups are more preferred, with t-butylbeing a most preferred group.

The present imidazo compounds have one chiral center which confersoptical activity. The optical isomers are designated conventionally as Land D, l and d, + and -, S and R or by combinations of these symbols.Where the formula or compound name herein carries no specificdesignation, the formula or name includes the individual isomers, themixtures thereof and racemates.

The imidazo compounds of Formula I-V where R is H, phenyl, cyano or CF₃,R₁ and R₂ are halogen, alkyl, --SCF₃ or said alkylene groups, R₃ is Hand R₄ is C₃₋₄ branched alkyl, especially t-butyl, are preferred. Thecompounds where R is cyano are particularly preferred, especially whenthe cyano group is ortho to the --OZ moiety.

Preferred compounds are the imidazopyridines of Formulae I and II, andespecially those having the formula ##STR5## More preferred VI and VIIIcompounds have the R group ortho to the --OZ group. Most preferredcompounds have R₃ =H and R₄ =t-butyl.

Especially preferred imidazopyridines have the formula ##STR6##Compounds of formula VIII where R is H or CN, R₁ and R₂ are H, Cl or C₁-C₆ alkyl, --SCF₃ or joined as --(CH₂)₃ -- or --(CH₂)₄ -- are morepreferred and where R is hydrogen, R₃ is hydrogen and R₄ is C₃ -C₄branched alkyl, especially t-butyl, the compounds are particularlypreferred.

Other preferred compounds are the imidazopyridines of formula V andespecially those having the formula ##STR7## Preferred R is H or CN.Preferred R₁ and R₂ are H, C₁ -C₆ -alkyl, --SCF₃ or Cl or joined as--CH₂)₃₋₄. Preferred R₃ is H and R₄ is C₃ -C₄ alkyl, especially t-butyl.

The imidazo compounds of the present invention may be prepared by anyconvenient process.

One such process involves the coupling of an imidazoazine or diazinewith a suitable substituted oxazolidine and hydrolyzing the reactionproduct obtained. This process is illustrated by the following set ofreaction equations: ##STR8## Halo may be Cl, Br and I, with Cl beingpreferred. M is H or alkali metal when XI is the reactant while M is anaryl or alkylsulfonyl group when XII is the reactant. Suitable bases areexemplified by K₂ CO₃, NaH, K--O--C(CH₃)₃, organic lithium such asn-butyllithium, phenyllithium, lithium diisopropyl amide etc. Y ishydrogen or a C₁ -C₁₂ alkyl or C₆ -C₁₂ aryl residue of any suitablealdehyde ##STR9## Examples of such aldehydes are arylaldehydes such asbenzaldehyde, naphthaldehyde, 4-phenylbenzaldehyde, tolualdehyde,nitrobenzaldehyde and the like, or alkanals such as acetaldehyde,butyraldehyde, ##STR10## and the like. The process for preparingoxazolidines (XIII; M═H) is disclosed in U.S. Pat. Nos. 3,718,647 and3,657,237 and to the extent necessary the pertinent disclosure isincorporated herein by reference. If it is desired to use alkali metalsalt of the oxazolidine, it may be prepared in a conventional manner byreaction of the corresponding hydroxymethyloxazolidine with anappropriate amount of a suitable alkali metal base.

The coupling reaction can be carried out at temperatures ranging fromabout 0° to about 100° C. A temperature range of about 10° to about 50°is preferred. The reaction is generally carried out in a solvent. Anysuitable solvent may be used. Examples of useful solvents are dioxane,toluene, tetrahydrofuran, dimethylformamide, dimethylsulfoxide,hexamethylphosphoramide, tert. butanol and the like. The hydrolysis iscarried out using conventional acid hydrolysis reagents and techniquese.g. treatment with a solution of any suitable acid such as CH₃ COOH,HCl or H₂ SO₄. The hydrolysis product can be directly obtained as thesalt of the acid used for the hydrolysis. Ordinarily, the product isrecovered as the free base after conventional neutralization of thesalt.

The coupling reaction is ordinarily carried out at atmospheric pressure.Higher pressures may be used if desired.

When a racemic oxazolidine (Formula XIII) is used as a reactant, theproduct is obtained as a racemate. The racemate may be separated intoits individual enantiomers by conventional resolution techniques.

When R₄ is the oxazolidine (Formula XIII or XIV) is other than hydrogen,in addition to the chiral center at oxazolidine position 5 there is asecond chiral center at position 2. However, whenever the oxazolidine isdesignated e.g. as (S), (R) or (R,S), this designation refers only tothe optical configuration around the carbon atom at the 5 position.

By using a single optical isomer of said oxazolidine in the abovereactions, the product may be obtained directly as a single enantiomer.Thus, if the S-isomer of the oxazolidine is used, then the productobtained will be the S-isomer. This provides a convenient way fordirectly preparing individual isomers of the present pyridines.

Imidazoazines and diazines of the present invention wherein R₃ is otherthan hydrogen are conveniently prepared by treating the correspondingcompound where R₃ is hydrogen with an appropriate acylating agent suchas an acyl halide, e.g. undecanoyl chloride, pivaloyl chloride,benzoychloride, p-methoxybenzoyl chloride, an anhydride e.g. aceticanhydride, and the like. The reaction is illustrated by the followingequation: ##STR11##

The compounds of the present invention also include the pharmaceuticallyacceptable salt of the novel imidazoazine or diazine. These salts areconveniently prepared e.g. by treating the imidazo compound with anappropriate amount of a useful acid, generally in a suitable solvent.

Another process for preparing the imidazo compounds having a cyanosubstituent is by halogen displacement as illustrated by the followingequation: ##STR12## The CN⁻ supplying reagent may be any suitable metalsalt such as CuCN, AgCN etc. Solvents which may be used are examplifiedby dimethylformamide, pyridine, 2,4-lutidine and the like. The reactionis generally carried out at elevated temperature, preferably in the100°-180° C. range.

Additional processes for preparing imidazo compounds with certain othersubstituents are illustrated by the following equation sequences.Conventional reaction conditions are employed. The desired othersubstituent is underlined. ##STR13##

The imidazo compounds having an alkylsulfinyl or alkylsulfonylsubstituent are prepared by oxidizing the corresponding C₁ -C₆ alkylthiocontaining compound. Any suitable oxidizing agent, e.g. H₂ O₂, may beused. The following equation illustrates the reaction ##STR14##

The compounds of the present invention have β-adrenergic blockingactivity. This β-adrenergic blocking activity was determined bymeasuring the ability of representative imidazo compounds to blockisoproterenol induced β-adrenergic stimulant effects such as heart rateincrease, hypotension and bronchodilation, in an animal.

The observed β-adrenergic blocking activity of these imidazo compoundsindicates that they are useful in humans which are benefited byβ-blockade such as angina pectoris, arrhythmia etc.

Some imidazo compounds of the present invention also haveantihypertensive activity of rapid onset. This antihypertensive activityis believed to be the result of peripheral vasodilation via a mechanismnot directly related to the β-adrenergic blockade. Thus, these dualacting compounds provide an additional advantage over the ordinaryβ-adrenergic blocking agent by having immediate antihypertensive effect.

This rapid onset antihypertensive activity is determined byadministering a representative imidazo compound to spontaneouslyhypertensive (SH) rats and measuring the effect on blood pressure.Representative compounds which were also found to have thisantihypertensive activity are listed in the following table:

                  TABLE I                                                         ______________________________________                                        Rapid Onset Antihypertensive Compounds                                        Compound                       Administration                                 Formula .sup.1○                                                                 R.sub.1       R.sub.2 Mode .sup.2○                            ______________________________________                                        A        SCF.sub.3     H       i.p.; p.o.                                     A        CH.sub.3      CH.sub.3                                                                              i.p.; p.o.                                     A        (CH.sub.2).sub.4  i.p.; p.o.                                         B        H             H       i.p.; p.o.                                     A        Cl            H       i.p.                                           ______________________________________                                         .sup.1○ Formula A is                                                   ##STR15##                                                                     and                                                                           Formula B is                                                                  ##STR16##                                                                     .sup.2○ i.p. = intraperitoneal; p.o. = oral                       

For use as antithypertensives and/or β-adrenergic blocking agents, thecompounds of the present invention can be administered orally orparenterally i.e. intavenously, intraperitioneally, etc. and in anysuitable dosage form. The compounds may be offered in a form (1) fororal administration e.g. as tablets in combination with othercompounding ingredients (diluents or carriers) customarily used such astalc, vegetable oils, polyols, benzyl alcohols, starches, gelatin andthe like-- or dissolved, dispersed or emulsified in a suitable liquidcarrier-- or in capsules or encapsulated in a suitable encapsulatingmaterial; or (2) for parenteral administration, dissolved, dispersed, oremulsified in a suitable liquid carrier or diluent. The ratio of activeingredients (present imidazo compound) to compound ingredients will varyas the dosage form requires. Conventional procedures are used to preparethe pharmaceutical formulations.

The daily dosage level for the present compounds as β-adrenergicblocking agents may be varied from about 0.01 mg. to about 100 mg. perkilogram of body weight. Daily doses ranging from about 0.01 to about 50mg/kg. are preferred, with about 0.01 to about 1.25 mg/kg being a morepreferred range. Oral administration is preferred.

The daily dosage level for the present compounds as antihypertensiveagents may be varied from 1 mg/kg. to 50 mg/kg. A preferred daily dosagerange is 1 to 25 mg/kg.

Either single or multiple daily doses may be administered depending onunit dosage.

The following examples illustrate the preparation of representativecompounds of the present invention. All parts are by weight unlessotherwise noted. All temperatures are °C.

Example 1 illustrates the preparation of intermediates used in preparingthe imidazo compounds of the present invention.

EXAMPLE 1 (A) 3-Trifluoromethylthio-5-bromo-imidazo[1,2a]pyridine

A solution of 14.1 g. (0.072 mol.) of 5-bromoimidazo[1,2a]pyridine in 90ml. tetrahydrofuran is stirred at -10° C. under nitrogen and treatedwith a steam of gaseous ClSCF₃ distilled from an ampoule. The mildlyexothermic reaction is maintained 1 hour at -10°-0°, warmed cautiouslyto +10° and then room temperature, and filtered. The cake isrecryatallized from absolute ethanol to give 4.0 g. white, solidhydrochloride of 3-trifluoromethylthio-5-bromo-imidazo[1,2a]pyridinecompound, m.p. 205°-206° C.

The 3-trifluoromethylthio-5-bromo-imidazo[1,2a]pyridine base is obtainedfrom the hydrochloride by extraction from aqueous sodium carbonate withCH₂ Cl₂ and sublimation of the residue from evaporation of the extractsto give 1.5 g. crystals, m.p. 59°-60° C.

(B) 3,5-Dibromoimidazo[1,2a]pyridine

5-Bromoimidazo[1,2a]pyridine (6.0 g., 0.032 moles) is added to asolution of 6.0 g. (0.034 mol.) of N-bromosuccinimide in 50 ml. coldchloroform. After a mild exotherm the mixture is aged 2 hours at roomtemperature and then percolated through a column of 75 g. silica gel.The column is eluted with chloroform to give a light orange fractionwhich is concentrated in vacuo and the residue sublimed to give 6.25 g.3,5-dibromoimidazo[1,2a]pyridine, m.p. 92°-94° C.

(C) 3-Chloro-5-bromoimidazo[1,2a]pyridine

A suspension of 5-bromoimidazo-[1,2a]pyridine (6.0 g., 0.031 mol.) and 5g. N-chlorosuccinimide in 50 ml. carbon tetrachloride is heated to theboiling point for 20 minutes, cooled, and filtered. The filtrate isconcentrated under vacuum to a dark solid which is dissolved in boilingethanol. The ethanol solution is treated with charcoal, filtered, andthe cooled filtrate chromatographed on 75 g. silica gel. The3-chloro-5-bromoimidazo[1,2a]pyridine (4.5 g.) is eluted with chloroformand purified by sublimation, m.p. 99°-101° C.

(D) 3-Trifluoromethyl-5-bromoimidazo[1,2a]pyridine

To a stirred solution of 2-amino-6-bromopyridine (5.2, 0.030 mol.) in 50ml 1,2-dimethoxyethane is added 11.3 g (0.06 mol)1,1,1-trifluoro-3-bromo-2-propanone at room temperature. The mixture isstirred 18 hours and filtered to give 10.9 g. of2-(1,1,1-trifluoro-2-keto-1-propaneamino)-6-bromopyridine hydrobromide,m.p. 250° C. dec. This hydrobromide is dissolved in 25 ml.trifluoroacetic acid and the solution treated with 25 ml.trifluoroacetic anhydride. The mixture is stirred 3 hours at roomtemperature, concentrated under vacuum and the residual oil carefullyneutralized with dilute aqueous sodium bicarbonate at ice temperature.The precipitated 3-trifluoromethyl-5-bromoimidazo[1,2a]pyridine (6.6 g.)is purified by sublimation, m.p. 130°-132° C.

(E) 2,3-Dimethyl-5-bromoimidazo[1,2a]pyridine

A mixture of 10.4 g. (0.060 mol.) of 6-bromo-2-aminopyridine and 9.0 g.(0.06 mol.) of 3-bromo-2-butanone in 40 ml. ethanol is refluxed 6 hoursand then kept 18 hours at room temperature. The mixture is diluted withfour volumes of ether to precipitate the hydrobromide of2,3-dimethyl-5-bromoimidazo[1,2a]pyridine, 6.0 g., m.p. 270°-272°. The2,3-dimethyl-5-bromoimidazo[1,2a]pyridine, 4.4 g., m.p. 69°-71°, isobtained by partitioning the crude hydrobromide between chloroform andaqueous sodium carbonate and sublimation of the CHCl₃ soluble material.

(F) 1-Bromo-6,7,8,9-tetrahydropyrido[1,2a]bnezimidazole.HBr ##STR17##

Similarly 2-chlorocyclohexanone (4.0 g., 0.03 mol.) is reacted with6-bromo-2-aminopyridine (5.2 g., 30 mmol.) in 30 ml. isopropanol for 18hours at reflux to give 4.7 g. of white crystals of1-bromo-6,7,8,9-tetrahydropyridoimidazo[1,2a]benzimidazole hydrobromide,m.p. 268°-269° C., after treatment with 4 ml. of 48% aqueous hydrobromicacid.

(G) 8-Phenyl-5-chloroimidazo[1,2a]pyridine

A mixture of 13 ml. of bromoacetaldehyde diethylacetal water (13 ml.)and 40% aqueous hydrobromic acid is refluxed vigorously for 1.5 hours,cooled, diluted to 300 ml. with 1,2-dimethoxyethane and treated with 33g. of sodium bicarbonate. After carbon dioxide evolution ceases themixture is filtered and the filtrate treated with 12.2 g. (0.595 moles)of 6-chloro-3-phenyl-2-aminopyridine. The resulting mixture is refluxedfor 16 hours, concentrated under vacuum and the residue dissolved in 50ml. trifluoroacetic acid. The dark solution is treated with 20 ml.trifluoroacetic anhydride and stirred 3 hours at room temperaturefollowing the exotherm. The mixture is concentrated under vacuum and theresidue is partitioned between ethyl acetate and aqueous sodiumcarbonate. The ethyl acetate extract is dried over sodium sulfate,filtered and concentrated under vacuum to an oil which is treated with10 ml. of 40% aqueous hydrobromic acid in 100 ml. isopropanol. Thecrystallized hydrobromide of 8-phenyl-5-chloroimidazo[1,2a]pyridine,11.0 g., m.p. 243°-245° C. is converted to8-phenyl-5-chloroimidazo[1,2a]pyridine as Step (A.), for example, and8-phenyl-5-chloroimidazo[1,2a]-pyridine purified, by recrystallizationfrom hexane, 8.4 g., m.p. 66°-68° C.

(H) Hydroxyimidazo[1,2a]pyridine

A solution of bromoacetaldehyde in 200 ml. absolute ethanol preparedfrom 20 g. of the diethylacetal as in (Step G.) is treated with 7.1 g(0.065 mol.) of 2-amino-3-hydroxy pyridine and the mixture refluxed 3hours, cooled, treated with styrenepolyamine ion-exchange resin untilthe solution is neutral and then filtered. The filtrate is concentratedto 75 ml. under vacuum and 6.0 g. of 8-hydroxyimidazo[1,2a]pyridine,m.p. 175° C., collected by suction.

EXAMPLE 2 (A) S-8-3-tert.Butylamino-2-hydroxypropoxy)imidazo[1,2a]pyridine sesquioxalatehemihydrate

A solution of S-2-phenyl-3-tert. butyl 5-hydroxymethyloxazolidine (8.8g., 0.040 mol) is converted to 13.6 g. of its crude tosylate bytreatment with 7.12 g. p-toluenesulfonylchloride in 14 ml. pyridine at20°-30° for four hours, followed by benzene extraction from aqueouspotassium carbonate.

8-Hydroxyimidazo[1,2a]pyridine (4.72 g., 0.035 mol.) is converted to itssodium salt with 1.48 g. of 50% NaH-mineral oil in 7 ml.N,N-dimethylformamide and the resulting solution is treated with saidcrude tosylate in 13 ml. N,N-dimethylformamide. The resulting mixture isheated to 100°-105° with stirring under nitrogen for 6 hours, quenchedin ice water, and extracted with chloroform. The chloroform extracts arewashed with water, extracted with 1.2 N aqueous hydrochloric acid andthe aqueous acid extracts basified with sodium hydroxide and extractedwith 1.2 N aqueous hydrochloric acid and the aqueous acid extractsbasified with sodium hydroxide and extracted with ethyl acetate. Theethyl acetate extract is dried over sodium sulfate, concentrated andchromatographed on neutral alumina. S-8-(3-tert.Butylamino-2-hydroxypropoxy)imidazo[1,2a]pyridine, 1.2 g., is elutedwith 1% methanol in chloroform and treated with a solution of 0.45 g.oxalic acid in hot ethanol. S-8-(3-tert.Butylamino-2-hydroxypropoxy)imidazo[1,2a]pyridine sesquioxalatehemihydrate, m.p. 157°-158°, crystallizes from the solution and iscollected by suction.

(B) S-5-(3-tert. Butylamino-2-hydroxypropoxy)imidazo[1,2a]pyridinedihydrochloride

A stirred suspension of 1 g. of about 50% by weight sodiumhydride-mineral oil emulsion washed free of oil with hexane bydecantation under nitrogen in 40 ml. N,N-dimethylformamide is treatedwith 4.71 g. (0.020 mol) of S-2-phenyl-3-tert.butyl-5-hydroxymethyloxazolidine and the mixture stirred at roomtemperature for 2 hours until hydrogen evolution ceases. The mixture istreated with 3.94 g. (0.020 mol.) of 5-bromoimidazo[1,2a]pyridine inportions. The mixture is stirred 1 hour at room temperature, quenched inice water and extracted with ether. The combined ether extract is washedwith water and extracted with two 12.5 ml. portions of 1.2 N aqueoushydrochloric acid. The combined aqueous acid extract is heated 30minutes on the steam bath, extracted with benzene to removebenzaldehyde, basified with sodium hydroxide and the base ofS-5-(3-tert.butylamino-2-hydroxypropoxy)imidazo[1,2a]pyridinedihydrochloride extracted with ethylacetate. The ethyl acetate extractis dried over sodium sulfate, filtered and concentrated under vacuum toan oil which is treated with 6 ml. ethanolic hydrogen chloride in 50 ml.isopropanol to give a dihydrochloride. Recrystallization from ethanolether gives 3 g. of S-5-(3-tert.butylamino-2-hydroxypropoxy)imidazo[1,2a]pyridine dihydrochloride, m. p.196°-197°.

Additional imidazopyridines of the present invention were prepared usingthe procedure of Example 2 B.) but substituting the appropriate Example1 intermediate for the 5-bromoimidazo[1,2a[pyridine reactant. Thecompounds and intermediates are tabulated below.

                  TABLE 2                                                         ______________________________________                                        Compounds of Formula                                                           ##STR18##                                                                             Formula                                                              Intermediate                                                                           C Compound                                                           of Example 1                                                                           R      R.sub.2                                                                              R.sub.1                                                                             X.sup.1○                                                                         M.P. (°C.)                      ______________________________________                                        (A)      H      H      SCF.sub.3                                                                           Free Base 135-6.5                                (B)      H      H      Br    . 2HCl . 2H.sub.2 O                                                                     > 350                                  (C)      H      H      Cl    . 2HCl . 1/2 H.sub.2 O                                                                  200 dec.                               (D)      H      H      CF.sub.3                                                                            . 2HCl . H.sub.2 O                                                                      147-48                                 (E)      H      CH.sub.3                                                                             CH.sub.3                                                                            2HCl . 1/2 H.sub.2 O                                                                    200-01                                 (F)      H      (CH.sub.2).sub.4                                                                         Free Base 154-55                                   (G)      C.sub.6 H.sub.5                                                                      H      H     . 2HCl . H.sub.2 O                                                                      185-87                                 ______________________________________                                         .sup.1○ the salts, where indicated, were prepared by treating the      free base with HCl in ethanol or ethanolisopropanol.                     

EXAMPLE 3 S-8-(3-tert. Butylamino-2-hydroxypropoxy)imidazo[1,2a[pyrazine dihydrochloride hemihydrate

Following the procedure of Example 2 B, 2.4 g. (0.01 mol),S-2-phenyl-3-tert. butyl-5-hydroxymethyloxazolidine is treated with 0.5g. (0.01 mol) of a 50% by weight sodium hydride-mineral oil emulsion in20 ml. N,N-dimethylformamide. To the resulting solution cooled to 0° isadded 1.75 g. of a mixture of 8-chloro- and 8-bromoimidazo[1,2a]pyrazine(about 0.01 mol.) with stirring under nitrogen. Workup, after 18 hoursat room temperature with aqueous 1.2 N hydrochloric acid, extraction ofhydrolyzed benzaldehyde with benzene, basification with aqueous sodiumhydroxide and extraction with chloroform, gives the free base ofS-8-(3-tert. butylamino-2-hydroxypropoxy)-imidazo[1,2a]pyrazinedihydrochloride hemihydrate. The crude base is converted to the hydrogenmaleate salt in acetonitrile and then to the hydrochloride via the freebase by treatment with hydrogen chloride in isopropanol. TheS-8-(3-tert. butylamino-2-hydroxypropoxy)imidazo[1,2a]pyrazinedihydrochloride hemihydrate, melts at 196°-197°.

EXAMPLE 4 S-5-(3-tert.Butylamino-2-hydroxypropoxy)-imidazo[1,2a]pyrazine dihydrochloridedihydrate

Following the procedures of Example 2 B 3.07 g. (0.020 mol) of5-chloroimidazo[1,2a]pyrazine is added to a solution of 1.0 g. 50% byweight sodium hydride-mineral oil emulsion (0.02 mol) and 4.70 g. (0.020mol) of S-2-phenyl-3-tert. butyl-5-hydroxymethyloxazolidine in 40 ml.N,N-dimethylformamide with stirring at 0°-5° under nitrogen. Workup,after 1 hour at room temperature, with 1.2 N aqueous hydrochloric acid,extraction of hydrolyzed benzaldehyde with benzene, basification withaqueous sodium hydroxide, and extraction with chloroform gives the freebase of S-5-(3-tert. butylamino-2-hydroxypropoxy) imidazo[1,2a]pyrazinedihydrochloride dihydrate. Treatment of the free base with hydrogenchloride in ethanol gives S-5-(3-tert.butylamino-2-hydroxypropoxy)imidazo[1,2a]pyrazine dihydrochloridedihydrate, m.p. 127°-129°.

Examples 5 and 6 illustrate the preparation of intermediates used inExamples 3 and 4.

EXAMPLE 5 5-Chloroimidazo[1,2a]pyrazine

A mixture of bromoacetaldehyde diethylacetal (13 ml.), water (1.3 ml.)and 40% aqueous hydrobromic acid (3.3 ml.) is refluxed 1.5 hours undernitrogen. The mixture is cooled, diluted with 300 ml. isopropanol,treated with sodium bicarbonate (33.3 g.) and filtered to give asolution of bromoacetaldehyde which is treated with6-chloro-2-aminopyrazine (8.0 g., 0.062 mmol) at reflux for 18 hoursunder nitrogen. The mixture is concentrated to one-third volumn undervacuum and treated with 4 ml. 40% aqueous hydrobromic acid. The mixtureis treated with fresh isopropanol and reconcentrated to give acrystalline hydrobromide salt of 5-chloroimidazo[1,2a]pyrazine, m.p.300°. The crude salt is partitioned between aqueous sodium carbonate andchloroform and the chloroform extracts treated with charcoal, filteredthrough diatomaceous earth, and concentrated under vacuum. The crude5-chloroimidazo[1,2a]pyrazine is sublimed to give 8.6 g. of yellowcrystals, m.p. 95°-95.5°, of 5-chloroimidazo[1,2a]pyrazine.

EXAMPLE 6 8-Chloro and 8-bromoimidazo[1,2a]pyrazine

The procedure of Example 5 is repeated substituting3-chloro-2-aminopyrazine and there is obtained a crude hydrobromide saltof 8-chloro and 8 bromoimidazo[1,2a]pyrazine mixture which ispartitioned between aqueous sodium carbonate and chloroform.Concentration of the dried chloroform extracts and vacuum sublimation ofthe residue gives 8.3 g. of a mixture of 8-chloro and8-bromoimidazo[1,2a]pyrazines, m.p. 176°-178°.

Claims to the invention follow.

What is claimed is:
 1. Compounds having the formula ##STR19## andpharmaceutically acceptable salts thereof wherein Z is --CH₂ --CHOR₃--CH₂ --NHR₄ wherein R is H or C₂ -C₁₂ acyl selected from alkanoyl,benzoyl, naphthoyl, methylbenzoyl and phenylbenzoyl and R₄ is C₁ -C₁₂alkyl,R is H, --SCF₃, --CN, halogen, C₁₋₆ alkyl, NH₂, C₁ -C₆ haloalkyl,C₁ -C₁₂ acyl, of the formula ##STR20## wherein L is H, alkyl or aryl,phenyl, --COOR₅ wherein R₅ is H C₁ -C₆ alkyl or C₆ -C₁₂ carbocyclicaryl, --CONR₆ R₇ wherein R₆ and R₇ when separate, are H or C₁ -C₆ alkyland when joined, are --CH₂ --(CH₂)₃ --CH₂, --CH₂ --CH₂ --O--CH₂ --CH₂--, --CH₂ --CH₂ --NH--CH₂ --CH₂ --, or --CH₂ --CH₂ --N(CH₃)--CH₂ --CH₂--, --C₁ -C₆ alkylthio, C₁ -C₆ alkylsulfinyl or C₁ -C₆ alkylsulfony, andR₁ and R₂ when separate are R and when joined are --(CH₂)_(n) -- whereinn is 3, 4 or
 5. 2. The compounds of claim 1 wherein R₃ is hydrogen andR₄ is C₃ -C₄ branched alkyl.
 3. The compounds of claim 2 wherein R₁ andR₂ are H, halogen,C₁ -C₆ alkyl, C₁ -C₆ acyl, --SCF₃ or --(CH₂)_(n) --wherein n is 3 or
 4. 4. Compounds of claim 3 wherein R is H, CN, phenylor CF₃.
 5. Compounds of claim 4 wherein R is in the position ortho tothe --OZ group.
 6. Compounds of claim 4 having the S-isomerconfiguration.
 7. Compounds of claim 1 having the formula ##STR21## 8.Compounds of claim 7 wherein R₃ is hydrogen and R₄ is C₃ -C₄ branchedalkyl.
 9. Compounds of claim 8 wherein R is hydrogen, CN or CF₃. 10.Compounds of claim 9 wherein R₁ and R₂ are H, halogen, --SCF₃, C₁ -C₆alkyl or --(CH₂)_(n) wherein n is 3 or
 4. 11. Compounds of claim 10wherein R is hydrogen.
 12. Compounds of claim 11 wherein R₁ and R₂ are--CH₂ --CH₂ --CH₂ --CH₂ -- and R₄ is t-butyl.
 13. Compounds of claim 7having the formula ##STR22##
 14. Compounds of claim 13 wherein R₃ ishydrogen and R₄ is C₃ -C₄ branched alkyl.
 15. Compounds of claim 14wherein R, R₁ and R₂ are each H and R₄ is t-butyl.
 16. Compounds ofclaim 7 having the formula ##STR23##
 17. Compounds of claim 16 whereinR₃ is H and R₄ is C₃ -C₄ branched alkyl.
 18. Compounds of claim 17wherein R, R₁ and R₂ are each H and R₄ is t-butyl.
 19. A pharmaceuticalcomposition for effecting β-adrenergic blockade containing an effectiveamount of a compound of claim 1.